Health care costs and resource use of managing hemophilia A: A targeted literature review

BACKGROUND: Hemophilia A (HA) is a rare, inherited, serious bleeding disorder characterized by a deficiency of blood clotting factor VIII (FVIII). HA is associated with considerable economic burden. OBJECTIVE: To identify, review, and summarize published studies on the health care resource use and costs of managing HA in the United States using a targeted literature review. METHODS: A comprehensive and targeted literature search was conducted in Embase, MEDLINE, and Cochrane Database of Systematic Reviews covering the period 2010 to 2022. We supplemented the search by searching gray literature (relevant abstracts, posters, and presentations of relevant scientific conferences from the past 6 years [2016 to 2022], reference lists, the Institute for Clinical and Economic Review reports, and other sources). Eligibility criteria were developed based on the population, interventions, comparators, and outcomes framework. For comparability, costs were adjusted to 2021 US dollars. RESULTS: A total of 40 publications, including 17 full-text papers, 21 abstracts, and 2 Institute for Clinical and Economic Review reports, met eligibility criteria. Total annual health care costs per patient ranged from $213,874 to $869,940 and are mainly driven by the cost and intensity of prophylaxis with FVIII replacement concentrates, bypassing agents, and, most recently, emicizumab. Generally, we observed substantial heterogeneity in estimated treatment costs for HA, which varied depending on HA severity, treatment type and intensity, age, weight, and inhibitor status. Patients with inhibitors incurred much higher costs, but annual FVIII treatment costs are increasing over time among a subset of adult patients without inhibitors. Only 2 studies reported indirect costs; these were $13,220 and $27,978 annually among patients without and with inhibitors, respectively. Parents of children with HA spent $8,252 on non–mental health services and $258 on mental health services annually. CONCLUSIONS: The annual health care costs of managing HA are substantial and vary widely, depending on the study population definitions and intensity of prophylaxis. Total health care costs are dominated by the cost of prophylaxis. Indirect costs are also important. More robust studies in various settings, subpopulations, and assessing the impact of emerging therapies are required to fully elucidate the changing societal and economic impact, particularly regarding indirect costs and productivity loss for individuals living with HA.


Plain language summary
Hemophilia A (HA) is a rare genetic condition affecting 32,000 male patients in the United States. Plasma-derived and recombinant clotting factors reflect standard of care. Extended half-life products, newly approved nonfactor agents (eg, emicizumab), and gene therapies in development are contributing to changes in care management. With new therapies, the impact on costs needs to be better understood. We have summarized the published literature on the substantial costs and resource use of managing HA in the United States.

Implications for managed care pharmacy
The cost of managing HA is substantial and varies by disease severity, treatment type and intensity, age, weight, and inhibitor status. This study provides an in-depth analysis of current health care costs and resource utilization, providing a useful benchmark to understand the comparative cost-effectiveness of future therapies that may alter the costs of managing HA (eg, in-development gene therapies). This will have implications for clinical and coverage policies that guide managed care pharmacy benefits.
Health care costs and resource use of managing hemophilia A: A targeted literature review cost outcomes for patients with mild HA, which excluded patients with moderate and severe HA. 16 Patients with more severe disease often require more intense therapy and medical attention. Because of the wide array of available treatment strategies and data sources, these costs can vary. The objective of this targeted literature review was to identify, review, and summarize the published literature on the costs of managing congenital HA and to show the variation in resource use and costs.

SEARCH STRATEGY AND STUDY SELECTION
A targeted literature review was performed to identify published evidence on medical resource use and health care costs (direct and indirect costs) for the treatment and management of patients with HA. We defined the search strategy, study inclusion and exclusion criteria, and outcomes of interest in a prespecified protocol (Supplementary  Tables 1 and 2, available in online article).
Eligibility criteria were developed based on the population, interventions, comparators, and outcomes framework (Supplementary Tables 3-5). We included any retrospective or prospective studies conducted on patients with HA in the United States that reported costs and/or health care resource use in a real-world setting. The population of interest was all patients with congenital HA in the United States, including all ages and severities, regardless of inhibitor status or therapy type. Studies were excluded if patients with congenital HA were mixed with other patients with hemophilia (ie, hemophilia B or acquired HA). Clinical trials and economic models were excluded if they were not the original source of the resource use and cost data.
A comprehensive search using predefined search strategy was performed in Embase, MEDLINE, and the Cochrane Database of Systematic Reviews covering the period 2010 to 2022. The last date of search was November 22, 2021. The search was repeated (May 2022) to ensure that any new publications in the intervening months were included. We searched relevant abstracts, posters, and presentations of relevant scientific conferences from the past 6 years (2016 to 2022). A manual search of reference lists and the Institute for Clinical and Economic Review website was also completed to identify additional studies. Abstracts were excluded as duplicates if the full-text paper was also identified in the search.

REVIEW AND DATA EXTRACTION
A single reviewer completed study screening through title and abstract review based on the predefined inclusion and exclusion criteria. Full-text review and data extraction Congenital hemophilia A (HA) is a rare, inherited, X-linked coagulation disorder characterized by a deficiency of blood clotting factor (F)VIII. People living with HA demonstrate different health care resource use (HCRU) than those with hemophilia B (HB), requiring separate evaluations. Genetic assessment, coagulation tests, and factor assessments now make it possible to quickly and efficiently diagnose hemophilia, differentiate genotype, and predict the risk of inhibitor development. 1 Approximately 85% of people diagnosed with hemophilia have type A and most are male. Roughly 400 new cases of HA are diagnosed annually in the United States. Approximately 50%-60% of all patients with HA have severe disease (< 1% of normal FVIII activity; associated with high rates of spontaneous bleeding that may necessitate prophylactic treatment), are diagnosed within the first year of life, and present with clinically significant bleeding-related complications. 2 Patients with HA may experience chronic joint diseases from repeated bleeding into the joints, neurological damage, and damage to other organ systems.
The goal of treatment is to prevent bleeding and joint damage and empower patients to practice self-management. Per the World Federation of Hemophilia Guidelines for the Management of Hemophilia, the use of prophylaxis, or regular administration of therapeutic products aimed at maintaining hemostasis to prevent bleeding, is always recommended for people with severe disease (and for some with moderate disease) over episodic replacement therapy at the time of a bleed, although "on-demand" treatment is additionally recommended to treat a breakthrough hemorrhage. 3 Access to innovative therapies allows patients with HA to live as long as individuals without HA. A new generation of extended half-life (EHL) clotting factor concentrates and hemostasis rebalancing agents (first US Food and Drug Administration [FDA] approvals 2014-2015) have shown benefit in preventing bleeding episodes and maintaining hemostasis with longer treatment intervals than standard half-life (SHL) products, without loss of efficacy, reducing the need for on-demand blood products. 4,5 FDA approval of emicizumab in 2017 has provided an additional treatment option demonstrating lower annualized bleeding rates in patients with HA, thus substantially reducing the disease burden for patients with and without inhibitors and impacting the utilization and costs of other agents and health care resources. [6][7][8] On the near horizon are gene therapies that may provide a functional cure for HA. 9,10 The medical and pharmaceutical costs of treating and preventing bleeding episodes in patients with HA have previously been evaluated in various data sources (eg, claims databases, surveys, and chart reviews) to be substantial. [11][12][13][14][15] Peyvandi et al reviewed earlier studies on quality of life and Health care costs and resource use of managing hemophilia A: A targeted literature review on 20% of the included studies was conducted by 2 of the authors (Ms Chen and Dr Cheng) for standardization and calibration using an extraction form with predefined outcomes of interest. The remaining studies were reviewed and extracted by a single author. The second reviewer checked for accuracy and completeness. Discrepancies were resolved through discussion.

OUTCOMES AND ANALYSIS
Costs were adjusted to 2021 US dollars using the 2021 Consumer Price Index in Medical Care. 17 If no currency year was reported in the study, the latest year of the study period was assumed for the base year (eg, for a study that analyzed data from 2010 to 2020, we used 2020 for the cost adjustment). Cost outcomes were summarized into different categories: aggregated health care costs, drug costs, outpatient and emergency department (ED) costs, inpatient costs, other costs (cost associated with bleeding, home health, and other medical costs), and indirect costs. Resource use outcomes included drug utilization, inpatient visit, ED visit, outpatient visit, indirect resource use (work or school absenteeism), other resource use (treatment center utilization, home health visit, or other visit), and bleeding rate.

STUDY SELECTION
The initial electronic database search conducted on November 22, 2021, identified a total of 1,967 records across all sources, and another 30 records were identified through the manual search in other sources and repeated search in May 2022. After duplicate removal of 751 reports, 1,246 titles and abstracts were screened, and 82 studies were eligible for full-text review. A total of 42 records were excluded based on population, interventions, comparators, and outcomes criteria, which resulted in a total of 40 studies being included in the final analysis. The final list of publications comprised 17 full-text papers, 21 conference abstracts, and 2 Institute for Clinical and Economic Review reports and is reported in the PRISMA Diagram format (Figure 1).

DESCRIPTION OF FULL-TEXT PUBLICATIONS
A total of 17 full-text publications were included in the review, with 11 studies published between 2017 and 2022 and 6 studies published earlier between 2012 and 2016. Separation of these publishing dates was done, as FDA approval of emicizumab in 2017 may have triggered more studies looking at costs and resource use after 2017. Most of the full-text publications (n = 15) included patients with HA across severities. The remaining 2 studies focused on adult patients with severe and moderate to severe HA, respectively. The real-world studies adopted a variety of data sources, including MarketScan research database (n = 6), Optum research database (n = 3), chart review (n = 2), American Thrombosis and Hemostasis Network (ATHN) Registry (n = 2), Humana research database (n = 1), US Department of Defense database (n = 1), Premier inpatient database (n = 1), and survey questionnaire administered to patients and caregivers (n = 1). Of the 17 included full-text publications, the majority (n = 12) reported costs and HCRU data. Two studies only reported costs data and 2 studies only reported resource use data. Indirect costs and HCRU were assessed in 2 publications (Table 1).

MEDICAL COSTS
Among studies reporting total annual health care expenditures of managing HA, the total health care costs per patient averaged from $213,874 to $869,940 (Supplementary Table 6). The highest total annual health care costs were incurred by patients with HA and inhibitors who were treated with bypassing agents. 18 We observed substantial heterogeneity in estimated treatment costs for HA, which varied depending on the intensity of prophylaxis, the specific drug product, and population age. Patients treated prophylactically by various agents incurred different mean annual treatment costs, including SHL products (range: $762,609-$831,702), EHL products (range: $832,595-$1,122,194), plasma-derived products ($693,709), and emicizumab ($358,384). In addition, 2 studies conducted prior to the approval of emicizumab reported average annual treatment costs using bypassing agents stratified by age groups, which were estimated at $439,536 and $1,051,567 among pediatric patients covered by Medicaid and employer-sponsored insurance, respectively. 19,20 Average annual treatment costs for adult patients using bypassing agents were $378,072 and $632,258 among those who were covered by Medicaid and employersponsored insurance, respectively. One study estimated outpatient pharmacy costs per patient per month for activated prothrombin complex concentrate and recombinant activated FVII bypassing therapies, which translated into approximately $60,888 and $59,220 per patient per year, respectively. 18 After restricting the population to adult male patients with HA without inhibitors, we observed the highest annual FVIII treatment costs among patients who used EHL products in 2 studies ($942,860 and $717,435, respectively) compared with other FVIII therapies such as SHL and plasma-derived products ( Figure 2). 12,21 Furthermore, there appears to be an increasing trend in total annual factor costs over time, although study populations across studies may still be heterogeneous regarding geographical Health care costs and resource use of managing hemophilia A: A targeted literature review

EFFECT OF INHIBITOR STATUS ON MEDICAL COSTS
A total of 11 studies reported total health care and drug costs for patients with HA by inhibitor status or conducted subgroup analyses among patients with or without inhibitors ( Table 2). All studies conducted prior to the approval of emicizumab showed consistent findings that patients with inhibitors incurred much higher costs regarding both aggregated health care costs and drug costs. For example, one study revealed that patients with inhibitors incurred 3.3 times higher median aggregated health care costs including drug costs than those without inhibitors ($427,423 vs $129,014). 25 Guh et al found 4.8 times higher mean annual health care expenditures comparing those with and without inhibitors in a population with employer-sponsored insurance ($1,004,731 vs $177,711) and a 3.6 times higher distribution, payer types, and demographic characteristics because of different data sources. 12,15,21,22 Five studies recorded costs associated with outpatient and ED visits. 12,14,18,22,23 The annual outpatient costs averaged from $4,772 to $109,776 and from $828 to $3,929 for ED visits. The highest annual outpatient cost was incurred by patients who received bypassing therapy and used ambulatory services, which was 4 times higher than those who received factor replacement therapy ($109,776 vs $26,604). 18 In contrast, the median annual outpatient costs were similar ($6,420 vs $5,040). Six studies reported inpatient costs, which averaged from $12,336 to $237,648. 12,14,18,22,[23][24] Supplementary Table 6 summarizes the details of costs associated with treating bleeds, home health visits, and other medical costs in each study.

INDIRECT COSTS
Only 2 publications assessed indirect HCRU and its associated costs. Zhou et al reported information on absenteeism and imputed indirect costs using the human capital approach, which used wages as a proxy measure of work time output. 15,26 The average annual total indirect costs per patient were estimated at $13,220 and $27,978 among patients without and with inhibitors, respectively. Subgroup analysis results by disease severity and age groups are summarized in Supplementary

RESOURCE USE
We found a range of results with substantial variability. Of the 14 studies with HCRU (Supplementary Table 8), most studies reported more than 1 type (n = 10), which included utilization of FVIII concentrate (n = 6), [11][12][13]21,22,27 emicizumab (n = 1), 13 and bypassing agents (n = 3), 19,20,24 admission to hospitals (n = 10), 12,14,15,19,20,22,24,25,27,28 outpatient/physician office visits (n = 5), 12,21,22,27,28 ED visits (n = 8), 12,14,15,19,20,22,27,28 hemophilia expenditure in the Medicaid-insured population ($644,941 vs $154,123). 19,20 Only one study in pediatric patients reported on the use of emicizumab, which is now the recommended standard of care for people with HA with an inhibitor. 3 This study showed the total annual cost of prophylaxis among pediatric patients with inhibitors was $1,269,500 prior to using emicizumab and $337,910 after using emicizumab, a significant reduction in costs (P < 0.001). Among pediatric patients without inhibitors, the annual cost of prophylaxis was reduced from $466,880 to $363,362 following initiation of emicizumab (P = 0.009).    Health care costs and resource use of managing hemophilia A: A targeted literature review (FVIII replacement concentrates, bypassing agents, and emicizumab), especially for those with severe disease on continuous prophylaxis. Studies conducted consistently demonstrate much higher costs for patients presenting with inhibitors compared with those without inhibitors. Overall, 74%-96% of total health care costs were attributed to the cost of treatment, which varied depending on the presence of inhibitors, disease severity, and treatment agents. Studies of adult patients with HA consistently showed higher product costs because currently used treatments employ weight-based dosing. Because different studies used various definitions of disease severity, it is difficult to compare cost estimates across studies. However, treatment center (HTC) visits (n = 2), 21,27 and home health visits (n = 2). 12,22 Several studies reported clinical outcomes associated with hemophilia-related bleeding events, whereas 2 studies reported joint procedures and surgeries. 21,29

OVERALL COSTS
Health care costs for patients with HA are substantial and vary widely, depending on the study population definitions and the intensity of prophylaxis. Total health care costs are dominantly driven by the cost of prophylaxis Health care costs and resource use of managing hemophilia A: A targeted literature review indirect costs and productivity loss among various key subpopulations may be beneficial to fully determine the burden of illness associated with HA.

OVERALL RESOURCE USE
The most frequently examined resource use outcomes include the following: (1) annual counts of hospital stays and office, ED, and home health visits, (2) proportion of patients with at least 1 of these visits, (3) length of inpatient stays, and (4) proportion of patients on each type of treatment. Less focus is on treatment duration and dosing patterns, as administrative claims data lack details that would provide information on timing of actual administration of FVIII concentrate, the prescribed dose, or the use of FVIII for continuous or intermittent prophylaxis.
Although the presence of inhibitors is relatively uncommon (~25%-30% of patients with severe HA), studies have shown consistently higher rates of hospitalizations and ED visits. 19,20,24,25 LIMITATIONS Data on patients with HA are commonly aggregated across disease severity and/or mixed with a hemophilia B population. Furthermore, most studies used a variety of outcome measures, scales, and time points, with very few studies using consistent formats. Because of the diversity in reporting, direct comparisons and meta-analyses were not possible, despite our efforts to extract outcomes data for comparable populations. However, this restriction to select only relevant data for populations of patients with hemophilia A facilitated the clean extraction and comparison of costs across published literature. Risk of bias was not formally assessed in the included studies given that the goal of the targeted literature review was to consolidate the existing evidence and not use it to conduct a meta-analysis. Additionally, results of the conference abstracts were not discussed given the scope of the study; however, data were extracted, and the results are included in Supplementary Table 9.
Conducting administrative claims data analyses in a population of patients with hemophilia is challenging because of the relatively small patient population and limitations of diagnostic coding. Using validated algorithms can improve specificity of patient identification. 31 Disease severity and inhibitor status is not specified in the coding. Therefore, most studies reported outcomes in populations with various levels of disease severity, with inhibitor status assumed if bypassing agents were observed in the patients' data. Thus, it is difficult to determine the costs of illness by hemophilia severity level and inhibitor status in studies using claims data. On the contrary, observational studies using data Zhou et al reported total direct medical costs, clotting factor costs, and indirect costs among patients without inhibitors stratified by disease severity, with the highest total direct costs incurred by those with severe HA and on prophylaxis treatment (mean = $383,793; SD = $245,002). 15 The highest indirect costs came from those with severe HA and requiring on-demand treatment (mean = $22,241; SD = $34,201), compared with those with mild, moderate, or severe disease on prophylaxis.
Among patients without inhibitors, total costs and treatment costs varied by the type of treatment. One study found lower costs of prophylaxis and the total cost of bleeding events after initiating emicizumab. 13 Two studies examined the use of different prophylaxis products and compared prophylaxis treatment costs for moderate to severe and severe patients at HTCs using the ATHN dataset. 11,21 Both studies found the highest costs from those being treated with EHL products. The longitudinal study by Croteau et al also found that EHL prescribing continues to rise nationally, 11 which might explain our finding of potentially rising FVIII treatment costs over time. EHL products with longer half-lives require less frequent injections compared with SHL treatments and would consequently result in reduced prophylactic treatment burden for patients and caregivers. Nevertheless, how further growth in use of EHLs will be impacted by emerging non-factor replacements and gene therapies is unclear.
As expected, the additional health care costs associated with inhibitors can be substantial for those who have them. Clotting factor costs, especially agents that bypass inhibitors (bypassing agents), accounted for the majority of the total costs because of the amount of treatment required to stop bleeding among those with high titer inhibitors. The average total annual health care expenditures varied across 3 claims-based retrospective studies (ranged from $644,941 to $1,004,731) because of different insurance mix of the populations, with the lowest costs from those with Medicaid insurance and the highest costs from those with employer-sponsored insurance. [18][19][20] In addition, people with HA who develop an inhibitor are twice as likely to be hospitalized for a bleeding complication, which resulted in significantly higher inpatient costs than those without inhibitors. 23 Two full-text publications and one conference abstract reported indirect costs among patients with HA. 15,26,30 They found that HA is also associated with considerable indirect costs for both pediatric and adult patients, mainly due to school absenteeism among children, functional disability of adult patients, and underemployment of parents of affected children. HA is a costly disorder, not only because of its high medical expenses but also because of the high indirect costs incurred. Differential data in terms of Health care costs and resource use of managing hemophilia A: A targeted literature review

DISCLOSURES
Drs Solari and Thornhill are employees of Spark Therapeutics and Roche Group Shareholders. Ms Chen and Drs Cheng and Sullivan are employees of Curta, Inc. Spark Therapeutics paid Curta, Inc., to conduct the literature search. This study was funded by Spark Therapeutics. Spark Therapeutics was involved in the study design, collection, analysis and interpretation of data, article review, and the decision to submit the report for publication. Medical writing support was provided by Ashfield MedComms, an Inizio company. cost, which excludes the confidential discount rates and rebates agreed between drug manufacturers and payers. However, pharmacy claims are often able to tease apart the average wholesale price, actual payment to the pharmacy (ie, the discounted price paid by the insurer but not accounting for rebates), and the patient's out-of-pocket cost for the medication. 32 Furthermore, a few studies did not report currency year and/or adjust for medical inflation. In cases where a currency year was not reported, we adjusted for inflation using the last year of the study's follow-up period. Together, these factors complicate the understanding of the economic burden of managing HA with emerging treatment options.

Conclusions
The economic burden of HA is substantial to the US payers and caregivers. Cost estimates vary widely, depending on the study population definitions, the intensity of prophylaxis, and the presence or absence of inhibitors. In all studies, total health care costs are dominantly driven by the cost of prophylaxis (ie, FVIII replacement concentrates, bypassing agents, and emicizumab) especially for patients with inhibitors and noninhibitor patients with severe disease on continuous prophylaxis. Various subgroups add to the complexity of understanding the cost burden. More robust studies in various settings and subpopulations are crucial to fully elucidate the economic burden, particularly regarding indirect costs and productivity loss for patients with HA. Cost and resource studies should also incorporate the patient/caregiver/ societal perspectives. As new treatments for HA emerge, future research examining resource use and costs is required to inform subsequent economic studies. obtained from HTCs or electronic medical records have the advantage of containing richer clinical information.
Importantly, the definitions of prophylaxis vary across studies. For instance, one study defined 3 prophylaxis cohorts over a 12-month period (1) based on quantity of claims, requiring patients with 6 or more non-inpatient, non-ED FVIII claims with 15 or more days supply; (2) based on frequency of claims, requiring no supply gaps more than 60 days between dispensings; (3) based on days of coverage, requiring patients having at least 273 days supply. This study found that the highest costs come from the subgroup with the third definition of prophylaxis use, highlighting how different methods of identifying patients managed with FVIII prophylaxis influence the cost estimates observed. 10 Using validated algorithms can improve patient identification. 31 Cost categories associated with managing HA were defined differently in some studies, thus requiring attention when interpreting and comparing study findings. For instance, some studies included medical and pharmacy costs in the calculation of FVIII prophylaxis treatment costs, whereas others only examined aggregate drug spending. Use of FVIII concentrate can be reflected on either medical claims or pharmacy claims, depending on each patient's specific benefit design. Therefore, careful understanding of the data is needed to avoid double-counting or omitting certain treatment costs. Differences in cost estimates highlighted the importance of knowing the data granularity and cost benchmarks used. For example, the ATHN dataset lacks specific cost data (although it does have good information on disease severity). Therefore, such studies estimated annual costs of FVIII prophylaxis based on use and median wholesale acquisition